PROJECT SUMMARY The long-term goals of this project are to understand, at the cellular level, how the central nervous system selects and generates the neuronal activity patterns underlying movement. Specifically, this project focuses on determining the flexibility inherent in motor circuits that is expressed in response to input they receive from sensory neurons, hormones and modulatory projection neurons. This includes determining the cellular mechanisms underlying the aforementioned circuit flexibility. This work focuses on rhythmically active motor circuits, such as those underlying walking, breathing, and chewing. A well-defined small model system, the crab stomatogastric nervous system, will be used. Previous work has shown that the same general principles underlie the generation of rhythmic motor programs in all animals. This proposal aims to extend previous work by determining the roles of metamodulation (modulation of a modulatory action), sensory feedback and cotransmission on motor pattern generation using the well-defined gastric mill (chewing) motor circuit in the crab stomatogastric nervous system. Four hypotheses will be tested: (1) Comparable motor patterns generated by distinct CPG circuits respond differently to a hormonal input and a sensory input;(2) a peptide hormone differentially gates the same sensory (proprioceptor) input to two comparable motor patterns generated by distinct CPG circuits;(3) the same neuromodulator acts at multiple levels of a motor system, and (4) peptidergic modulation can be regulated by GABAergic cotransmission. These studies will be done using electrophysiological and pharmacological approaches to monitor and manipulate the activity of projection neurons, circuit neurons, motor neurons, sensory neurons and muscle fibers. A computer program called the Dynamic Clamp will be used to inject realistic versions of synaptic and ionic currents into single neurons. The stomatogastric system is one of the few biological systems in which a detailed intracellular analysis and manipulation of neuronal network activity, at the level of identified neurons and muscles, is possible. Thus, the proposed studies will provide a valuable template for understanding comparable events in the numerically larger and less accessible mammalian central nervous system. It will also facilitate understanding the sensory and motor dysfunctions that occur as a result of events such as spinal cord injury and stroke. PROJECT NARRATIVE The proposed studies will provide a cellular-level model biological system for understanding comparable events in the numerically larger and less accessible mammalian central nervous system. This includes providing insight into the functional consequences of sensory and motor dysfunctions that occur as a result of events such as spinal cord injury and stroke, when descending modulatory projections and or sensory feedback is compromised or their actions are altered.